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this hypothesis, Valitutti's group recently showed that helper T cells are indeed able
to scan several adjacent APCs, thereby selecting for the APC loaded with the highest
amount of antigen [33].
Assumption 3: Intercellular Signals are Bidirectional and potentially conflicting.
Due to the use of one-sided read-out systems in immune cell stimulation studies,
interactions between immune cells have often been regarded as unidirectional in terms
of information transfer. However, evidence is now accumulating that during immune
cell interaction there is an exchange of signals, leading to changes in behavior of all
cells involved. Numerous membrane-associated proteins that bind receptors on the
opposing cell surface have been shown to possess signal transduction capacity. This
process of “reversed signaling” is most obvious in members of the Tumor Necrosis
Factor (TNF) family members, like TNF, CD40L, FasL, TRAIL and others [34].
Although the interaction between APC and T cells has long been regarded as a
unidirectional process leading to a change in activation status of the T cell, potential
activation of signaling pathways within the APC during this interaction has been
tested sporadically. For example cross-linking of MHC class II molecules by TCR or
antibodies can lead to changes in adhesive capacity [35], apoptosis, or maturation
[36]. Also interactions between T cells and mast cells were found to be bidirectional,
with mast cells being able to activate T cells, and to release both granule-associated
mediators and cytokines as a result of interaction with T cells [24].
Another example of bidirectionality between immune cells is the interaction
between NK cells and DC [37]. During NK-DC interactions, activated NK cells can
induce DC maturation. Cytokines produced by activated DC, on the other hand,
enhance the proliferation, cytokine production and cytotoxicity of NK cells.
Assumption 4: An effector function takes place only if two cells have been
interacting for a characteristic amount of time.
This assumption has also been
receiving increasing experimental support. The signal strength of T cell stimulation
by APC can be determined by both the concentration of antigen, the presence of co-
stimulation and the duration of the T cell-APC interaction [38]. Prolonged interaction
with APC was shown to be important for both effective T cell priming [39] and
polarization of the T cell response, e.g. into different helper subsets [40]. Importantly,
in vivo studies also show that interaction times of CD4+ and CD8+ T cells with APC
are significantly increased in the presence of specific antigen compared to T cell-APC
interaction times in the absence of antigen [32]. It therefore seems realistic to assume
that in order to establish a productive contact, i.e. a contact that leads to induction of
T cell effector function, prolonged interaction between T cells and APC is a necessity.
Although for induction of a cytotoxic response by NK cells and CTL interaction times
can be much shorter than in the priming phase, a minimal duration of the interaction
between effector and target cell is nevertheless necessary in order to elicit effector cell
function [41]. There is a significant body of evidence that the assembly of an
immunological synapse occurs in stages (reviewed in [42, 43]). Thus, cells must
interact for a certain amount of time to elicit at least some types of responses.
Thus, cells require a finite amount of time and only after a characteristic time is an
effector function triggered.
